The long-term objective is to eluciate the functional relationship between the brain and its extracellular fluids - interstitial fluid (ISF) and cerebrospinal fluid (CSF). Completed work has confirmed classical concepts of a network of channels within brain, analogous to lymphatics, for drainage of ISF. The significance of this system for clearing polar compounds from brain has been emphasized. Proposed experiments would continue to examine ISF flow in normal nervous tissue; they would also evaluate further the functional significance of this flow, both with respect to its possible role in brain volume regulation and its relation to the immune system. Extracellular tracers are microinjected into the neuropil and the pathways and dynamics of ISF flow determined from the characteristics of tracer clearance from the tissue. Studies of ISF flow in normal brain tissue would compare the characteristics of flow from different CNS regions and estimate the rate of drainage into deep cervical lymph, via cranial nerve sheaths, in cat and rat. Experiments designed to evaluate bulk flow between ISF and CSF as a mechanism of ISF volume regulation would measure a) solute and solvent flows between brain and CSF, b) sodium fluxes across the blood-brain barrier, and c) tissue fluid and electrolyte concentrations under defined experimental conditions, including alterations in CSF hydrostatic pressure and plasma osmolality. In order to explore the relation of ISF drainage to the immune system, kinetics of antigen clearance from brain and appearance in CSF, plasma and lymph would be determined following intracerebral injection and the results correlated with the appearance of anitbody in plasma and CSF. Techniques include intracerebral microinjection, measurement of cerebrovascular permeability, ventriculo-cisternal perfusion, collection of deep cervical lymph, and quantitative autoradiography. Results would have wide applicability to CNS pathologies including conditions characterized by excess brain fluids (edema, hydrocephalus, spinal cord injury) and diseases of the immune system (autoimmunity, multiple sclerosis, CNS tumors).